CN101820932A - Iron ion releasing endoprostheses - Google Patents

Abstract

An endoprosthesis comprising a base portion and a source of Fe(II) ions that is compositionally distinct from the base portion and releasable from the endoprosthesis under physiological conditions.

Description

Endoprosthesis that releases iron ions

technical field

The present invention relates to endoprosthesis, more specifically relates to a kind of frame.

Background technique

The body contains a variety of passages, such as arteries, other blood vessels, and other body lumens. These channels are sometimes blocked or weakened. For example, a channel can be blocked by a tumor, restricted by a plaque, or weakened by an aneurysm. At this point, the channel can be reopened, enhanced, or even replaced with a medical endoprosthesis. A typical endoprosthesis is a tube placed inside a body cavity. Examples of endoprostheses include stents, covered stents, and stent-grafts.

The prosthesis may be delivered into the body using a catheter that supports the compressed or reduced size of the endoprosthesis to deliver the endoprosthesis to the desired site. Upon reaching the above-mentioned site, the endoprosthesis expands, for example to make contact with the wall of the lumen.

The expansion mechanism may include forcing the endoprosthesis to expand radially. For example, the expansion mechanism may include a catheter with a balloon that carries an endoprosthesis expandable with the balloon. The balloon is expandable and deformable, thereby fixing the expanded endoprosthesis at a predetermined position in contact with the lumen wall. The balloon can then be deflated, allowing the catheter to be removed.

In another method of delivery, the endoprosthesis is formed from an elastic material that is capable of reversibly compressing and expanding, such as elastically or through a material phase transition. During introduction into the body, the endoprosthesis is constrained in compression. After arriving at the desired implantation site, the constraint is removed by, for example, removing the constraint device such as the outer sheath, so that the endoprosthesis can self-expand by its own internal elastic recovery force.

Restenosis after implantation of an endoprosthesis can cause serious problems. Migration and proliferation of smooth muscle cells (SMCs) in response to initial injury with deposition of extracellular matrix is thought to be an important factor in causing restenosis.

Summary of the invention

An endoprosthesis is disclosed that includes a base portion and a source of Fe(II) ions that is compositionally distinct from the base portion and releasable from the endoprosthesis under physiological conditions.

In some embodiments, a source of Fe(II) ions may be implanted within the substrate portion. For example, the source of Fe(II) ions may be in the form of nanoparticles embedded within the substrate portion. In some embodiments, the base portion can have pores, and the source of Fe(II) ions can be stored within the pores. In some embodiments, the source of Fe(II) ions may be in the form of a layer covering a portion of the substrate. In some embodiments, the source of Fe(II) ions may be in the form of a guide wire. In some embodiments, the endoprosthesis may also include a drug-eluting coating covering the base portion. The drug eluting coating may include a source of Fe(II) ions. In some embodiments, an endoprosthesis can have a concentration gradient of Fe(II) ions.

In some embodiments, the source of Fe(II) ions can include metallic iron or alloys thereof. For example, the source of Fe(II) ions may include iron having a purity of at least 99%. The source of Fe(II) ions may also include alloys of iron and Mn, Ca, Si or combinations thereof. In some embodiments, the source of Fe(II) ions can be iron oxides, iron carbides, iron sulfides, iron borides, or combinations thereof. For example, the source of Fe(II) ions can include magnetite.

In some embodiments, the base portion can include a metal alloy. For example, the metal alloy may be stainless steel, platinum reinforced stainless steel, cobalt-chromium alloy, nickel-titanium alloy, or combinations thereof.

In some embodiments, the base portion may comprise a bioerodable material, such as a bioerodable metal (eg, magnesium or iron) or a bioerodable polymer. Examples of bioerodible polymers include: polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymer, modified cellulose, collagen, poly(hydroxybutyrate) , polyanhydrides, polyphosphates, poly(amino acids), poly-L-lactides, poly-D-lactides, polyglycolides, and poly(alpha-hydroxy acids).

In some embodiments, the endoprosthesis can also include a porous coating covering the base portion, the source of Fe(II) ions, or a combination thereof. For example, the porous coating can be a calcium phosphate hydroxyapatite coating, a sputtered titanium coating, a porous inorganic carbon coating, or combinations thereof.

In some embodiments, an endoprosthesis may be a stent.

A method of forming an endoprosthesis is also described. The method comprises the following steps: placing Fe(II) ions on the surface of the endoprosthesis, so that the obtained endoprosthesis is suitable for releasing Fe(II) ions under physiological conditions. For example, Fe(II) ions can be implanted by metal ion immersion implantation.

The details of one or more implementations are set forth in the accompanying drawings and the description below. Other features, objects and advantages will be apparent from the description, drawings and claims.

Description of drawings

Figure 1 is a perspective view of one example of an expanded stent.

Figure 2 is a perspective view of one example of an expanded stent having interwoven iron guide wires.

The same reference numerals in different drawings denote the same elements.

Detailed description of the invention

1, the stent 20 may be in the form of a tubular member defined by a plurality of ribbons 22 and a plurality of connectors 24 extending between and connecting adjacent ribbons. . For example, stent 20 in FIG. 1 may be a balloon expandable stent. In use, the ribbon 22 can expand from an initial smaller diameter to a larger diameter to bring the stent 20 into contact with the vessel wall, thereby maintaining the vessel patency. Connectors 24 impart elasticity and compliance to stent 20 so that the stent conforms to the contours of the vessel.

Stent 20 may include a base portion and a source of Fe(II) ions that is compositionally distinct from the base portion. The source of Fe(II) ions is releasable from the scaffold 20 under physiological conditions. The Fe(II) ions produced can inhibit at least some of the processes associated with cell proliferation. Thus, by providing a source of Fe(II) ions that are releasable from the stent 20 under physiological conditions, the resulting Fe(II) ions are released into the patient to inhibit smooth muscle cell proliferation, thereby reducing the likelihood of restenosis.

The source of Fe(II) ions can take a variety of forms. For example, the source of Fe(II) ions may be Fe(II) ions embedded in some portion of the stent 20 . As described below, one possible method of implanting Fe(II) ions into certain portions of the stent 20 is metal ion impregnation implantation (MPIII).

The source of Fe(II) ions may also be in the form of metallic iron or alloys thereof. For example, iron can be alloyed with Mn, Ca and/or Si, all of which are biocompatible. Some suitable ferrous alloys are described, for example, in US Patent 2,950,187 to Ototani. In some embodiments, the source of Fe(II) ions may be iron having a purity of at least 99%. Metallic iron or its alloys can be in the form of a coating covering the entire stent or a specified portion of the stent, in the form of nanoparticles embedded in the entire stent or in a specified portion of the stent, or even as a guide between the stent and the blood vessel. silk form. Iron nanoparticles of ultra-high purity (e.g., 99.999% iron by weight) are commercially available from American Elements, 1093 Broxton Ave. Suit 200, Los Angeles, CA 90024 (1093 Broxton Ave. Suit 200, Los Angeles, CA 90024). High-purity iron guide wire can be purchased from Goodfellow, trade name FE005105-iron guide wire diameter: 0.025mm, high purity: 99.99+% toughness (Iron Wire Diameter: 0.025mm, High Purity: 99.99+% Temper ).

The source of Fe(II) ions may also be in the form of bioerodible iron-containing ceramics or iron salts. Examples include iron oxides, iron carbides, iron sulfides, iron borides, or combinations thereof. In some embodiments, the source of Fe(II) ions may be in the form of magnetite (Fe ₃ O ₄ ). With the degradation of magnetite, two Fe(III) ions can be provided for every Fe(II) ion provided, so that the controlled release of Fe(II) ions can be realized. Magnetite can be nano-sized or micron-sized particles.

The base portion of the stent can be either bioerodible or non-bioerodable material. The bioerodable substrate portion may be a bioerodable metal and/or a bioerodable polymer. For example, the base portion may comprise magnesium or alloys thereof. The base portion may also be pure iron, for example iron having a purity of at least 99%. Examples of bioerodible polymer base moieties include: polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymer, modified cellulose, collagen, poly(hydroxybutyrate ester), polyanhydride, polyphosphate, poly(amino acid), poly-L-lactide, poly-D-lactide, polyglycolide, poly(alpha-hydroxy acid), or combinations thereof. In some embodiments, the bioerodible substrate portion can be substantially free of iron. The non-bioerodible base portion may include metal alloys such as stainless steel, platinum reinforced stainless steel, cobalt-chromium alloys, nickel-titanium alloys, or combinations thereof.

The source of Fe(II) ions may be in the form of a layer covering part of the substrate. The source of Fe(II) ions can be metallic iron or a bioerodible iron alloy. The base portion may be a bioerodible metal or a non-bioerodable material. A method of producing an outer layer of iron on a base portion includes sputtering iron onto the base portion. Another possible method of producing an iron layer on the substrate part involves using pulsed laser deposition (PLD) or inverse pulsed laser deposition (inverse PLD).

The source of Fe(II) ions may also be incorporated into a layer of another material covering the substrate portion. For example, the source of Fe(II) ions can also be in the form of nanoparticles embedded in bioerodable metals or bioerodable polymers, or Fe(II) ions embedded in bioerodable metals or bioerodable polymers . The source of Fe(II) ions may also be stored in the pores of the layer covering the substrate portion. In some embodiments, the aforementioned layer may be a drug-eluting coating covering the substrate portion. For example, a source of Fe(II) ions can be embedded in a conventional polymeric (eg SIBS) drug-eluting coating. In other embodiments, the source of Fe(II) ions may be in the form of nanoparticles embedded in the drug eluting coating, or the drug eluting coating may have pores filled with the source of Fe(II) ions. After the release of Fe(II) ions from the drug eluting coating and the erosion of the source of Fe(II) ions from the drug eluting coating, the drug eluting coating can become more porous, thereby enhancing drug release of the remaining drug molecules .

The source of Fe(II) ions may be in the form of Fe(II) ions embedded in the substrate portion. For example, Fe(II) ions can be implanted through MPIII. By using MPIII, iron ions can be implanted into complex three-dimensional structures. By using MPIII, a layer implanted with Fe(II) ions, a metallic iron layer or a combination thereof can be obtained. By using MPIII, a concentration gradient of Fe(II) ions can also be created within the substrate portion. In some embodiments, a secondary iron coating process may be performed after the Fe(II) ion-implanted MPIII treatment.

For a magnesium or magnesium alloy substrate, an iron layer on top of the magnesium substrate can retard corrosion of the magnesium substrate under physiological conditions. Therefore, magnesium-iron scaffolds can be designed not only to inhibit smooth muscle cell proliferation, but also to erode over a desired period of time. For example, the outer layer of a magnesium stent may have up to 94% by weight iron infused into the magnesium or magnesium alloy. By using MPIII, it is also possible to gradually transition iron to magnesium, thereby providing smaller interface stress between magnesium and iron layers.

By using a layer-by-layer approach, magnesium-iron struts can be formed. Fe ions can be implanted into the magnesium substrate by MPIII, and then additional layers of magnesium and iron can be formed by PLD and MPIII. This layer-by-layer approach provides additional corrosion protection for magnesium and supplies Fe(II) ions throughout the lifetime of the scaffold.

Fe(II) ions can also be placed into bioerodible polymer scaffolds by ion implantation methods such as rotating the polymer scaffold on top of a metal support, resulting in a bioerodible polymer implanted with Fe(II) ions base part.

The source of Fe(II) ions may be in the form of nanoparticles or microparticles embedded in the substrate portion. As noted above, these nanoparticles or microparticles may include metallic iron or alloys thereof, ferrous ceramics or iron salts (such as nanoparticles of magnetite or 99.999% pure iron).

Nanoparticles or microparticles can be incorporated into the substrate moiety by a variety of methods. For example, scaffolds can be formed by mixing nanoparticles or microparticles into a melt of a biodegradable polymer. Another example includes adding particles to various shells in a layer-by-layer approach. The concentration of nanoparticles or microparticles may vary between layers. Nanoparticles of a source of Fe(II) ions can also be embedded in the substrate part by generating a stream of charged nanoparticles, placing the substrate part on an electrode, supplying power to the electrode so that it has the opposite polarity to the charged particles, and then placing the substrate Partially placed in the aforementioned stream of charged nanoparticles. A charged nanoparticle stream can be formed by forming a nanoparticle-containing solution, spraying the solution with a charged nozzle, and allowing the solution to evaporate. A more detailed description of similar methods of embedding nanoparticles into polymeric medical devices can be found, for example, in US Patent 6,803,070 to Weber.

The base portion may have pores in which the source of Fe(II) ions may be stored. The base portion may be a bioerodible metal, or may also be a non-bioerodable metal. The corrosion rate of Fe(II) ions can be controlled by depositing a source of Fe(II) ions in the pores of the substrate portion.

The scaffold may comprise a porous coating covering the source of Fe(II) ions or covering a portion of the substrate. The porous coating may be an inorganic coating such as a calcium phosphate hydroxyapatite (CaHA) coating, a sputtered titanium coating, or a porous inorganic carbon coating. By providing a porous coating, direct contact of corroded iron with endothelial cells covering the scaffold is avoided.

In the embodiment shown in FIG. 2 , the source of Fe(II) ions may be in the form of a guide wire 42 . As shown, guidewire 42 is interwoven with the body of stent 40 . At least a portion of the bracket 40 forms a base portion. A guidewire may be positioned between the stent and vessel, feeding iron through iron corrosion. This embodiment can achieve a more uniform distribution of iron within the tissue. For example, very thin guidewires may be used that form a denser network than the stent itself. High-purity iron guide wire can be purchased from Gu Tefu Company, trade name FE005105-iron guide wire diameter: 0.025mm, high purity: 99.99+% toughness (Iron Wire Diameter: 0.025mm, High Purity: 99.99+% Temper). The source of Fe(II) ions may also be a bioerodible iron alloy.

Stent 20 may be of a desired shape and size (eg, coronary stent, aortic stent, peripheral vascular stent, gastrointestinal stent, urological stent, and neurological stent). Depending on usage, stent 20 may have a diameter of, for example, 1 mm to 46 mm. In certain embodiments, a coronary stent may have an expanded diameter of 2 mm to 6 mm. In certain embodiments, the peripheral vascular stent may have an expanded diameter of 5 mm to 24 mm. In certain embodiments, a gastrointestinal stent and/or a urological stent may have an expanded diameter of 6 mm to 30 mm. In certain embodiments, the neurological scaffold can have an expanded diameter of 1 mm to 12 mm. Abdominal aortic aneurysm (AAA) stents and thoracic aortic aneurysm (TAA) stents can have a diameter of about 20 mm to 46 mm. Stent 20 may be a balloon-expandable stent, a self-expanding stent, or a combination of both (eg, US Pat. No. 5,366,504).

系统，得自波士顿科学医学科技(Boston Scientific Scimed)公司，明尼苏达州马普勒格罗韦(Maple Grove，MN)。In use, the stent 20 may be delivered and expanded using a catheter delivery system. Catheter systems are described, for example, in US Patent 5,195,969 to Wang, US Patent 5,270,086 to Hamlin, and US Patent 6,726,712 to Raeder-Devens. Stents and stent delivery are also exemplified

system from Boston Scientific Scimed, Maple Grove, MN.

Stent 20 may be part of a covered stent or a stent-graft. In another embodiment, the stent 20 may comprise and/or be attached to a biocompatible, non-porous or semi-porous polymer matrix composed of polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene Made of vinyl fluoride, polyethylene, urethane or polypropylene.

Embodiments described herein may be used to form other endoprostheses such as guide wires or hypotubes.

All publications, documents, applications and patents cited herein are hereby incorporated by reference in their entirety.

Other implementations are within the scope of the following claims.

Claims (25)

1. An endoprosthesis comprising a base portion and a source of Fe(II) ions that is compositionally distinct from said base portion and releasable from said endoprosthesis under physiological conditions . 2. The endoprosthesis of claim 1, wherein the source of Fe(II) ions is placed within the base portion. 3. The endoprosthesis of claim 1, wherein the source of Fe(II) ions is in the form of nanoparticles embedded within the base portion. 4. The endoprosthesis of claim 1, wherein the base portion has pores, and the source of Fe(II) ions is stored in the pores. 5. The endoprosthesis of claim 1, wherein the source of Fe(II) ions is in the form of a layer covering the base portion. 6. The endoprosthesis of claim 1, wherein the source of Fe(II) ions is in the form of a guide wire. 7. The endoprosthesis of claim 1, further comprising a drug-eluting coating covering said base portion, said drug-eluting coating including said source of Fe(II) ions. 8. The endoprosthesis according to claim 1, characterized in that there is a concentration gradient of Fe(II) ions in the endoprosthesis. 9. The endoprosthesis of claim 1, wherein the source of Fe(II) ions comprises metallic iron or alloys thereof. 10. The endoprosthesis of claim 1, wherein the source of Fe(II) ions comprises iron having a purity of at least 99%. 11. The endoprosthesis of claim 1, wherein the source of Fe(II) ions comprises an alloy of iron with an element selected from the group consisting of Mn, Ca, Si, and combinations thereof. 12. The endoprosthesis of claim 1, wherein the source of Fe(II) ions is selected from the group consisting of iron oxides, iron carbides, iron sulfides, iron borides, and combinations thereof. 13. The endoprosthesis of claim 1, wherein the source of Fe(II) ions comprises magnetite. 14. The endoprosthesis of claim 1, wherein said base portion comprises a metal alloy selected from the group consisting of stainless steel, platinum reinforced stainless steel, cobalt-chromium alloys, nickel-titanium alloys, and their combination. 15. The endoprosthesis of claim 1, wherein the base portion comprises a bioerodible material. 16. The endoprosthesis of claim 1, wherein said base portion comprises magnesium. 17. The endoprosthesis of claim 1, wherein said base portion comprises iron. 18. The endoprosthesis of claim 1, wherein said base portion comprises a bioerodible polymer selected from the group consisting of polydioxanone, polycaprolactone , polygluconate, polylactic acid-polyethylene oxide copolymer, modified cellulose, collagen, poly(hydroxybutyrate), polyanhydride, polyphosphate, poly(amino acid), poly-L-lactate Esters, poly-D-lactides, polyglycolides, poly(alpha-hydroxy acids), and combinations thereof. 19. The endoprosthesis of claim 1, further comprising a porous coating covering the base portion, a porous coating covering the source of Fe(II) ions, or a combination thereof combination. 20. The endoprosthesis of claim 19, wherein said porous coating is selected from the group consisting of calcium phosphate hydroxyapatite coatings, sputtered titanium coatings, porous inorganic carbon coatings, and combinations thereof combination. 21. The endoprosthesis of claim 1, wherein said endoprosthesis is a stent. 22. An endoprosthesis, characterized in that it comprises: a base portion comprising magnesium or an alloy thereof; and a source of Fe(II) ions, said source of Fe(II) ions being different from the base portion and available at Released from the endoprosthesis under physiological conditions; the source of Fe(II) ions includes metallic iron or its alloys. 23. The endoprosthesis according to claim 22, characterized in that there is a concentration gradient of Fe(II) ions in the endoprosthesis. 24. A method of forming an endoprosthesis, comprising the steps of: Implanting Fe(II) ions on the surface of an endoprosthesis or a precursor thereof renders the resulting endoprosthesis suitable for releasing said Fe(II) ions under physiological conditions. 25. The method of claim 24, wherein the Fe(II) ions are implanted by metal ion immersion implantation.

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